Children’s brain tumors more diverse than previously believed

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May 14, 2012

Pediatric brain tumors preserve specific characteristics of the normal cells from which they originate – a previously unknown circumstance with ramifications for how tumor cells respond to treatment. This has been shown by Uppsala researcher Fredrik Swartling together with colleagues in the United States, Canada, and England in a study that was published today in the journal Cancer Cell.

The discovery improves the prospects for finding more effective treatments for forms of pediatric cancer that are currently very difficult to cure and has great significance for understanding how brain tumors arise. The next step is to carry out the clinical analyses necessary for developing drugs that target specific types of brain tumors.

Trials were carried out using immature cells, or stem cells, from such regions of the brain as the cerebellum, cerebrum, and brainstem. The stem cells were then compared with tumor cells from more than 100 patients. Cellular origin showed itself to be at least as important a determinant of tumor malignancy as the genetic mutations underlying the transformation of normal cells to tumor cells. The point in time at which tumors arose was also of great relevance to the effectiveness of treatment.

"We can't focus exclusively on mutated genes when looking at cancer," says Fredrik Swartling, who directed the study jointly with pediatric neurologist William Weiss, who works at the University of California children's hospital and brain tumor research center in San Francisco, California. "The status of the cells of origin giving rise to cancer is at least as important from a treatment standpoint. Our study shows that tumors contain markers for these cells of origin."

Brain tumors most often arise on account of accidental genetic mutations. One gene that mutates readily and is well-represented in pediatric brain tumors is the MYCN cancer gene. Previous research has proposed that patients with high levels of a specific cancer gene like MYCN should be treated in the same way. The current study shows that this is not the case.

"The tumors are more diverse that we believed," Fredrik Swartling says. "It is very important, even for patients who exhibit the exact same mutation of a cancer gene, whether their tumors arose in the cerebellum, cerebrum or brainstem and whether these tumors arose during fetal stages or following birth."

The researchers showed in the study that normal stem cells are transformed into brain tumor cells in vitro following introduction of the MYCN cancer gene to the cells. Stem cells from an early fetal stage and from a later life juncture were both transformed into tumor cells. The effectiveness of treatment differed, despite the fact that the same cancer gene had caused the tumors in each case.

That tumors reflect their origins makes it relatively simple to determine the origin of the cancer represented in a tumor biopsy from a patient. The challenge ahead will be to identify reliable markers for tumor origin to enable better judgment about treatment options and ensure the effectiveness of treatment in diverse cases.

"The goal is to develop a range of different treatments for patients of different types," Fredrik Swartling says. "It may take some time before such treatments are available at hospitals, but clinical trials involving drugs similar to those used in the study are already under way, and we are keeping our fingers crossed that the drugs will work as anticipated."

The study was financed by the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, and the Swedish Research Council, among other sources.